Blood concentrations of enflurane before, during, and after hypothermic cardiopulmonary bypass.

OBJECTIVE: The purpose of this study was to determine blood concentrations of enflurane delivered via a membrane oxygenator during hypothermic cardiopulmonary bypass (CPB) with changes in the input enflurane concentration and temperature and to characterize the pharmacokinetics of enflurane washout during and after CPB. DESIGN: Blood enflurane concentrations were measured by gas chromatography before, during, and after CPB by using mean delivered enflurane concentrations of 0.5% v/v (group 1, n = 5), 0.8% (group 2, n = 7), and 1% (group 3, n = 14). SETTING: The investigation was performed in a teaching hospital setting. PARTICIPANTS: Twenty-six patients undergoing cardiac surgery requiring hypothermic CPB. INTERVENTIONS: Variations in input enflurane concentration in different patients plus blood sampling from the arterial side of the circuit for enflurane assay. MEASUREMENTS AND MAIN RESULTS: Median (25th and 75th percentiles) pre-CPB blood enflurane concentrations were 48 (25-50) mg/L, 52 (47-56) mg/L, and 115 (90-143) mg/L in groups 1 (0.5% v/v), 2 (0.8% v/v), and 3 (1% v/v), respectively. During hypothermia (28 degrees C) corresponding enflurane concentrations were 44 (31-53) mg/L, 56 (45-62) mg/L, and 145 (109-203) mg/L, respectively. For groups 1 and 2, there were no significant changes in blood enflurane compared with the corresponding pre-CPB value. However, for group 3, cooling resulted in a significant increase (p = 0.006) in blood enflurane. In all groups, enflurane concentrations after rewarming were similar to those in the pre-CPB period. CONCLUSIONS: It is concluded that exposure to enflurane concentrations greater than 0.8% during CPB can result in high blood concentrations.

Tissue solubility of four volatile anesthetics in fresh and frozen tissue specimens from swine.

OBJECTIVE: To determine tissue solubilities of desflurane, sevoflurane, enflurane, and halothane in swine and to evaluate the effects of freezing specimens on tissue solubility, SAMPLE POPULATION: Arterial blood samples and specimens of brain, heart, liver, kidney, muscle, and subcutaneous fat from 5 healthy female adult Chinese Meishan pigs. PROCEDURE: Each tissue specimen was divided into 2 parts. One part was used to measure tissue-gas partition coefficients immediately after collection. The other part was frozen at -20 C for 6 days prior to determination of tissue-gas partition coefficients. Tissue-gas and blood-gas partition coefficients were measured by use of gas chromatography, and tissue-blood partition coefficients were calculated. Regression analysis was performed to determine whether fat-gas partition coefficients were correlated with lean tissue-gas partition coefficients. RESULTS: Tissue-gas and blood-gas partition coefficients of halothane were greater than those of enflurane followed by coefficients of sevoflurane and desflurane. However, the order of anesthetic agents with the greatest to smallest tissue-blood partition coefficients was sevoflurane, halothane, enflurane, and desflurane. Muscle-gas partition coefficients of sevoflurane and enflurane, liver-gas partition coefficients of desflurane and halothane, and the kidney-gas partition coefficient of enflurane were significantly greater in frozen specimens, compared with fresh specimens. Lean tissue-gas partition coefficients of all 4 volatile anesthetics correlated directly with fat-gas partition coefficients. CONCLUSIONS AND CLINICAL RELEVANCE: The fat content of lean tissue is an important factor in determining the tissue solubility of volatile anesthetics. Freezing specimens before determination of tissue-gas partition coefficients may result in a false increase in tissue solubility.

Sensitive determination of four general anaesthetics in human whole blood by capillary gas chromatography with cryogenic oven trapping.

Four general anaesthetics, sevoflurane, isoflurane, enflurane and halothane, in human whole blood, have been found measurable with very high sensitivity by capillary gas chromatography-flame ionization detection (GC-FID) with cryogenic oven trapping upon injection of headspace (HS) vapor sample. To a 7-ml vial, containing 0.48 ml of distilled water and 20 microl of internal standard solution (5 microg), a 0.5-ml of whole blood sample spiked with or without anaesthetics, was added, and the mixture was heated at 55 degrees C for 15 min. A measure of 10 ml HS vapor was injected into the GC in the splitless mode at -40 degrees C oven temperature, which was programmed up to 250 degrees C. All four peaks were clearly separated; no impurity peaks were found among their peaks. Their extraction efficiencies were about 10%. The calibration curves showed good linearity in the range of 0.5-20 microg/ml; their detection limits were 10-100 ng/ml, which are almost comparable to those by previous reports. The coefficients of intra-day and day-to-day variations were 6.5-9.8 and 7.3-17.2%, respectively. Isoflurane or enflurane was also measured from whole blood samples in which three volunteers inhaled each compound.

Effect of temperature on the solubility of desflurane, sevoflurane, enflurane and halothane in blood.

We have investigated the effect of temperature on the blood-gas solubility of desflurane, sevoflurane, enflurane and halothane. Blood was equilibrated with gas mixtures of known composition in open cuvette or closed flask tonometers over a temperature range of 29-39 degrees C, and the concentration of each anaesthetic in blood was measured at 37 degrees C by repeated headspace analysis using a gas chromatograph. Solubility increased by 5.4% of the solubility at 37 degrees C for each degree that equilibration temperature was reduced. This result was true for all anaesthetics in all blood samples, and is in keeping with results for other volatile anaesthetics.

Simple and rapid determination of enflurane in human tissues using gas chromatography and gas chromatography-mass spectrometry.

A simple, rapid and reliable method was devised to determine the levels of enflurane in human tissues, using gas chromatography and gas chromatography-mass spectrometry. 1,4-Dioxane was used as an internal standard (I.S.). Enflurane and the I.S. were extracted from 0.25 g of body tissues using an automatic headspace sampler and 1 ml of headspace gas was injected into the gas chromatograph. Enflurane was analyzed qualitatively by gas chromatography-mass spectrometry and quantitatively by gas chromatography with a flame-ionization detector. The calibration curves in all tissues examined were linear in the concentration range 1-100 microg/0.25 g. The lower limit of detection was 200-300 ng/0.25 g. The accuracy and precision of this method were evaluated at two different concentrations, 1 and 20 microg/0.25 g. The coefficient of variation ranged from 3.4-13.4%. We used this method to determine the presence of enflurane in tissues from an autopsied individual who died suddenly during extirpation of a malignant tumor.

Quantitative study of Lowe's square-root-of-time method of closed-system anaesthesia.

Intermittent injection of liquid anaesthetic into a closed breathing system is particularly suitable in countries with limited resources. A method of calculating appropriate times and magnitudes of the injected doses was described by Lowe but the method has never been assessed rigorously. Such an assessment was the purpose of this study. The technique was used in a double-blind, randomized comparison of halothane, enflurane and isoflurane in oxygen-air, with 20 ASA I or II patients in each group, undergoing superficial or abdominal surgery. The prescribed times of injection were adhered to, but the doses, after the first two, were adjusted to maintain systolic arterial pressure within 20% of the reference preoperative value. Partial pressures of the anaesthetics were monitored but concealed from the investigator-anaesthetist. The mean doses found necessary for each anaesthetic were within 33% of those calculated to produce 1.3 MAC. However, end-tidal partial pressure (just before each dose) stabilized at a steady level of only 0.97, 0.42 and 0.77 MAC for halothane, enflurane and isoflurane, respectively. Recovery from enflurane was much more rapid than that from the other agents but no patient admitted to any dreams. We conclude that the rate of uptake of anaesthetic declines more slowly than predicted and that the patients receiving enflurane were less deeply anaesthetized because the greater hypotensive effect of enflurane led to the use of smaller doses.

Determination of the volatile anesthetics halothane, enflurane, isoflurane, and sevoflurane in biological specimens by pulse-heating GC-MS.

Four kinds of volatile anesthetics (halothane, enflurane, isoflurane, and sevoflurane) that were dissolved in 3 microL of experimental plasma samples were examined by the pulse-heating gas chromatographic-mass spectrometric method, and this approach was found to be reliable for qualitative and quantitative analysis. The analytical results also showed good recovery and accuracy. This method was then applied to real blood specimens taken from patients during surgery. The same blood specimens were also analyzed simultaneously by the conventional headspace method for comparison. The data for the clinical blood specimens examined by these two methods showed reasonable correlation coefficients of 0.914 (enflurane) and 0.937 (sevoflurane). These results indicate that the pulse-heating method is applicable for toxicological and clinical analysis of several kinds of volatile anesthetics.

Renal concentrating function with prolonged sevoflurane or enflurane anesthesia in volunteers.

BACKGROUND: Sevoflurane, a new inhalational anesthetic, is biotransformed, producing peak plasma inorganic fluoride concentrations that may exceed 50 microM. We evaluated plasma inorganic fluoride concentrations with prolonged (> 9 MAC-h) sevoflurane or enflurane anesthesia in volunteers and compared renal concentrating function with desmopressin testing 1 and 5 days after anesthesia. METHODS: Fourteen healthy male volunteers received either enflurane or sevoflurane (1-1.2 MAC) for more than 9 MAC-h. Each volunteer was administered three tests of renal concentrating function, with intranasal desmopressin and urine collections performed 1 week before anesthesia and 1 and 5 days after anesthesia. Venous blood samples were obtained for plasma fluoride concentrations during and after anesthesia. Creatinine clearance was determined by 24-h urine collections 7 days before and 4 days after anesthesia. Urine samples were obtained before and 1, 2, and 5 days after anesthesia for determination of n-acetyl-beta-glucosaminidase and creatinine concentrations. RESULTS: Prolonged sevoflurane anesthesia (9.5 MAC-h) did not impair renal concentrating function on day 1 or 5 postanesthesia, as determined by desmopressin testing. Maximal urinary osmolality on day 1 postanesthesia was decreased (< 800 mOsm/kg) in two of seven enflurane-anesthetized volunteers; however, mean results did not differ from the those of the sevoflurane group. Mean peak plasma fluoride ion concentrations were 23 +/- 1 microM 6 h postanesthesia for enflurane and 47 +/- 3 microM at the end of anesthesia for sevoflurane (P < 0.01). There were no changes in creatinine clearance or urinary n-acetyl-beta-glucosaminidase concentration in either anesthetic group. DISCUSSION: Prolonged sevoflurane anesthesia did not impair renal concentrating function, as evaluated with desmopressin testing 1 and 5 days postanesthesia in healthy volunteers. Although with prolonged enflurane anesthesia, mean maximal osmolality values on day 1 postanesthesia did not differ from sevoflurane values, there was evidence in two volunteers at this time point of impairment in renal concentrating function, which normalized 5 days postanesthesia. These results occurred despite a higher peak plasma fluoride ion concentration and greater total inorganic fluoride renal exposure with sevoflurane anesthesia.

Clinical enflurane metabolism by cytochrome P450 2E1.

BACKGROUND: Fluorinated ether anesthetic hepatotoxicity and nephrotoxicity are mediated by cytochrome P450-catalyzed oxidative metabolism. Metabolism of the volatile anesthetic enflurane to inorganic fluoride ion by human liver microsomes in vitro is catalyzed predominantly by the cytochrome P450 isoform CYP2E1. This investigation tested the hypothesis that P450 2E1 is also the isoform responsible for human enflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. METHODS: Twenty patients undergoing elective surgery were randomized to receive disulfiram (500 mg orally; n = 10) or nothing (control subjects; n = 10) the evening before surgery. All patients received a standard anesthetic of enflurane (2.2% end-tidal) in oxygen for 3 hours. Blood enflurane concentrations were measured by gas chromatography. Plasma and urine fluoride concentrations were quantitated by ion-selective electrode. RESULTS: Patient groups were similar with respect to age, weight, gender, duration of surgery, and blood loss. Total enflurane dose, measured by cumulative end-tidal enflurane concentrations (3.9 to 4.1 MAC-hr) and by blood enflurane concentrations, was similar in both groups. Plasma fluoride concentrations increased from 3.6 +/- 1.5 mumol/L (baseline) to 24.3 +/- 3.8 mumol/L (peak) in untreated patients (mean +/- SE). Disulfiram treatment completely abolished the rise in plasma fluoride concentration. Urine fluoride excretion was similarly significantly diminished in disulfiram-treated patients. Fluoride excretion in disulfiram-treated patients was 62 +/- 10 and 61 +/- 12 mumol on days 1 and 2, respectively, compared with 1090 +/- 180 and 1200 +/- 220 mumol in control subjects (p < 0.05 on each day). CONCLUSIONS: Disulfiram prevented fluoride ion production after enflurane anesthesia. These results suggest that P450 2E1 is the predominant P450 isoform responsible for human clinical enflurane metabolism in vivo.

Hemodynamic interactions when combining verapamil, acute changes in extracellular ionized calcium concentration and enflurane, halothane or isoflurane in chronically instrumented dogs.

To assess the hemodynamic interactions when combining verapamil, acute changes in extracellular ionized calcium concentration [Ca2+] and enflurane (2.5%), halothane (1.2%) or isoflurane (1.6%), seven dogs were chronically instrumented to measure heart rate (HR), aortic, left atrial and left ventricular (LV) pressures, and cardiac output (CO). [Ca2+] was lowered 0.35 mmol.l-1 by citrate infusion and then increased 0.35 mmol.l-1 above control level by CaCl2 infusions. Verapamil was infused at 3 micrograms.kg-1 x min-1 (loading dose 200 (awake), 150 (isoflurane) or 100 (enflurane and halothane) micrograms.kg-1), giving mean verapamil concentrations around 75 (range of means: 66-84 ng.ml-1). Verapamil produced mostly minor changes in the cardiovascular effects of changing [Ca2+] in both awake and anesthetized dogs, indicating mostly additive effects. Verapamil induced a decrease in HR at high [Ca2+] and abolished an increase in mean aortic pressure at both low and high [Ca2+] awake. Verapamil exaggerated the decrease in CO and stroke volume (SV) induced by low [Ca2+] during enflurane anesthesia and abolished the increase in CO induced by low [Ca2+] and exaggerated the increase in SV and LV dP/dtmax induced by high [Ca2+] during halothane anesthesia.

[The effects of arterial blood halothane or enflurane concentration on the circulatory system].

The effects of halothane (H) or enflurane (E) concentration on the circulatory system were studied in dogs. Two hours of halothane or enflurane anesthesia resulted in a linear dose-dependent decrease in circulatory indices including mean arterial pressure (mAP), cardiac index (CI) and left ventricular peak dp/dt/IP (peak dp/dt/IP). Systemic vascular resistance (SVR) was unchanged during either anesthesia. The correlations between the percent change of circulatory indices and the logarithm of the blood anesthetic concentrations were expressed by correlation coefficients (r): mAP, r = -0.718 (H), and -0.650 (E): HR, r = -0. 329 (H), and -0.352 (E): CI, r = -0.597 (H), and - 0.596 (E): SI, r = -0.389 (H), and -0.449 (E): SVR, r = -0.161 (H), and -0.030 (E): peak dp/dt/IP, r = -0.708 (H), and -0.871 (E). Using several indices of anesthetic depth including MAC, MAC-EI and MAC-BAR, the percent changes of mAP, CI and peak dp/dt/IP were calculated at the same anesthetic depth using halothane or enflurane. These results indicate that enflurane depresses these circulatory indices more than halothane. The differences were: mAP, 14.51 +/- 1.46%: CI, 8.14 +/- 1.86%: peak dp/dt/IP, 7.38 +/- 3.95% (mean +/- SD).

Blood/gas solubility coefficient and blood concentration of enflurane during normothermic and hypothermic cardiopulmonary bypass.

The blood/gas solubility coefficient and blood concentration of enflurane were measured at intervals in 10 patients undergoing coronary artery revascularization with cardiopulmonary bypass (CPB) and moderate hypothermia. A constant end-tidal concentration of enflurane was maintained throughout the study. Blood/gas solubility coefficient was determined at 37 degrees C, which when combined with an initial single-step equilibration of the blood sample with air, permitted the accurate measurement of blood concentration. Blood/gas solubility coefficient and blood concentration both decreased significantly with the onset of CPB. During the period of hypothermia, blood/gas solubility as measured at 37 degrees C showed little change; however, there was a progressive, marked increase in blood concentration with a mean increase of 80% prior to rewarming. Therefore, the level of anesthesia provided by enflurane may lighten with the onset of CPB, and a deeper level will accompany any decrease in blood temperature. On rewarming, blood concentration levels rapidly returned to levels similar to those measured before cooling. The increased uptake and accumulation of volatile anesthetic agent that occurred as a result of the period of hypothermic CPB was rapidly cleared. The rapidity with which blood concentration responded to the changes occurring during CPB make it unlikely that there was any significant increase in myocardial depression in response to the raised blood concentration secondary to the hypothermia.

Does cardiopulmonary bypass alter enflurane requirements for anesthesia?

This study on dogs determined whether the requirement for enflurane anesthesia was different pre- versus postcardiopulmonary bypass (CPB). Male mongrel dogs (n = 16) were anesthetized with enflurane in oxygen. Tracheal intubation was performed, monitors placed, and end-tidal enflurane concentration measured via a Puritan-Bennett Anesthesia Agent Monitor. MAC was determined by the tail-clamp method. CPB was then initiated using aortoatrial (n = 6, group 1) or femoral artery-vein (n = 4, group 2) cannulation or none (n = 6, group 3, control). CPB was maintained for 1 h using a bubble oxygenator, a crystalloid prime, and flows of approximately 70-80 ml/kg with a mean systemic pressure maintained between 50-70 mmHg. Following separation from CPB, MAC was again determined. The reduction in enflurane MAC following CPB was 30.1 +/- 21.5% (mean +/- SD; P less than 0.05 vs. pre-CPB) in group 1 but there was a wide range of reduction produced (3.8-58.8%). The degree of MAC reduction (19.8 +/- 8.6%; P less than 0.05 vs. pre-CPB) produced by CPB in group 2 was much less variable in degree (range 13.0-32.4%) but did not differ from group 1. Although pre- versus post-CPB mean systemic pressure fell from 83 +/- 13 to 69 +/- 15 mmHg (P less than 0.05), this is above the level likely to produce a reduction in MAC. No other significant hemodynamic changes were observed. Temperature pre- versus post-CPB was not different. The degree of hemodilution and acid-base disturbances are unlikely to be the explanation.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of enflurane and halothane in hypotensive eye surgery.

Thirty patients undergoing elective eye surgery had anaesthesia induced with sodium thiopentone, suxamethonium and d-tubocurarine chloride. Patients were ventilated with nitrous oxide, oxygen and either halothane or enflurane. The volatile agents were used to decrease the systolic blood pressure to 80 mmHg. The volatile agent concentration in the blood was measured at 30 min intervals. Both agents were effective in producing hypotension, but enflurane was the more potent hypotensive agent in terms of MAC equivalents. There was no significant differences between the agents with respect to speed of recovery.

Gas chromatographic determination of volatile anaesthetic agents in blood. Part 1. Preparation of standard gas mixtures of volatile anaesthetic agents.

A method for preparing standard gas mixtures of the volatile anaesthetics halothane, enflurane and isoflurane is described. Static mixtures of gases of known concentration can be prepared manometrically by measuring the required pressure of anaesthetic gas into a bulb and diluting to atmospheric pressure with air. Standard gas mixtures in the concentration range 0-4% V/V can be prepared with an accuracy of +/- 0.01% V/V, and the relative standard error of measurements of a single standard concentration is less than 0.8%. Significant adsorptive losses in the gas sampling valve were observed for gas standards prepared in the absence of any diluent gas. These losses were not detected for measurements of standards made up to atmospheric pressure in air. A comparison with calibration procedures currently in practice is presented.

Vaporizer for volatile anesthetics during high-frequency jet ventilation.

At present, the potent inhalation anesthetics cannot be used during high-frequency jet ventilation (HFJV) because a suitable vaporizer is not available. A vaporizer for enflurane during HFJV was designed, built, and tested, based on the principle of airblast atomization in which liquid enflurane is delivered to the vaporizer by an infusion pump. Eight dogs were kept anesthetized with enflurane for 2 h using this device. Vital signs and arterial blood gases were within normal limits during anesthesia. The concentration of vaporized enflurane, measured by mass spectrometry, could be reliably and accurately controlled within the clinical range at any minute volume by adjusting the infusion rate. Measurements of blood enflurane indicated that enflurane uptake could be adequately achieved.

In vitro anesthetic washin and washout via bubble oxygenators: influence of anesthetic solubility and rates of carrier gas inflow and pump blood flow.

The uptake and elimination of volatile anesthetic agents administered to patients under conditions of hemodilution and hypothermia during cardiopulmonary bypass have not been determined. To define the limitations imposed by oxygenators, we defined washin and washout curves for volatile anesthetic agents administered to bubble oxygenators primed with diluted blood (without connection to a patient). There was rapid equilibration of anesthetic partial pressure between delivered gas and blood (85-90% within 16 minutes). Increasing the gas inflow to the oxygenator from 3 to 12 L/min hastened washin and washout slightly, while increasing the pump blood flow from 3 to 5 L/min had no effect. Rates of washin and washout of anesthetics differed as a function of their blood/gas solubilities: enflurane greater than isoflurane greater than halothane during washin; isoflurane greater than enflurane greater than halothane during washout. However, these differences were small. Oxygenator exhaust partial pressures of anesthetic correlated with simultaneously obtained blood partial pressures, suggesting that monitoring exhaust gas may be useful clinically.

Prolongation of the QT interval by volatile anesthetics in chronically instrumented dogs.

The influence of volatile anesthetics on ventricular repolarization in vivo (QT interval) has not been studied in a systematic fashion. The purpose of this investigation was to characterize the electrocardiographic and hemodynamic actions of the volatile anesthetics halothane, isoflurane, and enflurane in chronically instrumented dogs. Because autonomic nervous system tone may influence ECG findings, experiments were completed with and without concomitant pharmacologic autonomic nervous system blockade. In six groups comprising 50 experiments with 21 instrumented dogs, anesthesia was mask-induced with nitrous oxide, oxygen, and one of the volatile anesthetics and maintained with the volatile anesthetic in 100% oxygen for 2 hours. Changes in the ECG and in hemodynamics were compared to the conscious state. In the absence of autonomic nervous system blockade, halothane and isoflurane significantly prolonged the QT interval (0.24 +/- 0.01 to 0.30 +/- 0.01 second and 0.22 +/- 0.01 to 0.28 +/- 0.01 second, respectively), whereas enflurane produced no change in ventricular repolarization (0.24 +/- 0.01 to 0.26 +/- 0.01 second). All of the volatile anesthetics increased the QT interval corrected for changes in basal heart rate (QTc), and all agents decreased intravascular pressure and dP/dt. Following autonomic nervous system blockade, halothane, isoflurane, and enflurane significantly increased the QT interval and QTc. The results demonstrate that ventricular repolarization is directly altered by the volatile anesthetics independent of changes in autonomic nervous tone. Whether or not such effects are additive with other congenital or acquired forms of QTc prolongation has yet to be examined. The present results indicate that caution should be used during the administration of volatile anesthetics to patients with abnormalities of the QT interval.

Direct determination of the blood concentration of halogenated anesthetic agents by gas chromatography.

The direct determination by gas chromatography of blood levels of anesthetic agents has been difficult because of the water content of blood. In the present study, the method of Yokota et al. (1967) was modified by improving the packing materials of the column, the blood sample vaporizer and the flow-path during analysis. As a result, accurate and reproducible determination of halothane, enflurane and isoflurane dissolved in blood was achieved. With this system, blood in which halothane, enflurane and isoflurane had been dissolved could be analyzed without changing the column between samples. Moreover, each sample was prepared in less than 10 min, and more than 100 consecutive determinations could be made with excellent reproducibility. The coefficient of variation was less than 3.8%.

Cardiac electrophysiologic interactions of bepridil, a new calcium antagonist, with enflurane, halothane, and isoflurane.

Bepridil is an investigational calcium antagonist that also has fast sodium channel blocking and antidysrhythmic properties. In the present study, the potential interactions of bepridil with volatile anesthetics on cardiac electrophysiologic parameters were evaluated in open-chest dogs. Twenty-four dogs anesthetized with enflurane (n=6), halothane (n=6), isoflurane (n=6), or chloralose (n=6) received 2.5 mg/kg of bepridil intravenously (IV). Twenty-five additional dogs anesthetized with enflurane (n=7), halothane (n=6), isoflurane (n=6), or chloralose (n=6), received bepridil, 5.0 mg/kg, IV. Dogs anesthetized with cloralose served as controls. Cardiac electrophysiologic parameters were measured after the dogs were anesthetized and were repeated 5, 15, 30, 45, and 60 minutes after bepridil infusion. Plasma bepridil concentrations were also determined at the above time points. Synergy between bepridil and enflurane was demonstrated in the following cardiac electrophysiologic parameters: depression of sinus node function as evidenced by severe depression of sinus node automaticity and conduction; depression of atrioventricular function as evidenced by prolongation of the atrial-His bundle interval and the Wenckebach R-R interval; and, prolongation of the atrial effective refractory period. No synergy was demonstrated between bepridil and halothane or isoflurane when compared to bepridil's effects during chloralose anesthesia. It is concluded that significant synergistic cardiac electrophysiologic effects exist between bepridil and enflurane in dogs. It is recommended that caution be used when anesthetizing patients receiving bepridil with enflurane until human data on the use of this combination of pharmacologic agents is available.